LETTER
The prevalence and incidence of nontuberculous mycobacterium (NTM) infections are increasing globally (1). However, treatment of NTM diseases remains difficult due to their resistance to most available antimicrobial agents; therefore, new antimicrobials are urgently needed (2).
Bedaquiline (BDQ), delamanid (DLM), and pretomanid (PA-824) are new drugs for the treatment of multidrug-resistant tuberculosis. Bedaquiline is a diarylquinoline agent that inhibits the mycobacterial ATP synthase (3), delamanid is a new agent derived from nitro-dihydro-imidazooxazole that inhibits mycolic acid synthesis (4), and pretomanid is a prodrug bicyclic nitroimidazole that has been approved for use in the treatment of nonresponsive multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis cases (5). In contrast to BDQ and DLM, no MICs of PA-824 have been reported for NTM. To compare the activities of these novel agents against various NTM species, we determined the MICs of clinical NTM isolates in China.
A total of 131 clinical isolates of five major pathogenic NTM from patients newly diagnosed with NTM-pulmonary disease were collected from a national drug resistance surveillance program. Isolates were characterized further by using matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry. In vitro drug susceptibility testing was performed by a microdilution MIC method according to guidelines from the Clinical and Laboratory Standards Institute (CLSI) (6). The MIC value is defined as the lowest concentration of an antibiotic that inhibits the visible growth of mycobacteria. MICs for rapidly growing mycobacteria were monitored after incubation for 3 to 5 days until sufficient growth was evident in the control well, while the slowly growing NTM were read after incubation for 7 to 14 days.
Table 1 shows the MIC, MIC50, and MIC90 values of BDQ, DLM, and PA-824 for 131 isolates. For BDQ, all isolates had very low MIC50 (≤0.125 μg/mL) and MIC90 (≤0.25 μg/mL) values, although the slowly growing mycobacteria Mycobacterium avium, M. intracellulare, and M. kansasii had lower MIC50 (0.03125 to 0.015 μg/mL) values than those for the rapidly growing mycobacteria M. abscessus and M. massiliense (0.125 μg/mL). Compared to these NTM, M. avium and M. abscessus had high MIC90 (0.25 μg/mL) values.
TABLE 1.
MIC and minimal bactericidal concentration values for bedaquiline, delamanid, and pretomanid in clinical NTM isolates
| NTM species (no. of isolates) and antibiotic | No. of isolates with MIC (μg/ml) of: |
MIC50 (μg/mL) | MIC90 (μg/mL) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.015 | 0.03125 | 0.0625 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | >16 | |||
| M. avium (13) | ||||||||||||||
| Bedaquiline | 9 | 1 | 1 | 2 | 0.015 | 0.25 | ||||||||
| Delamanid | 2 | 5 | 1 | 5 | 0.125 | >16 | ||||||||
| Pretomanid | 1 | 12 | >16 | >16 | ||||||||||
| M. intracellulare (16) | ||||||||||||||
| Bedaquiline | 16 | 0.015 | 0.015 | |||||||||||
| Delamanid | 1 | 2 | 3 | 1 | 9 | >16 | >16 | |||||||
| Pretomanid | 1 | 15 | >16 | >16 | ||||||||||
| M. kansasii (28) | ||||||||||||||
| Bedaquiline | 27 | 1 | 0.03125 | 0.03125 | ||||||||||
| Delamanid | 24 | 1 | 1 | 1 | 1 | 0.03125 | 0.125 | |||||||
| Pretomanid | 2 | 1 | 11 | 12 | 2 | 4 | 8 | |||||||
| M. abscessus (45) | ||||||||||||||
| Bedaquiline | 2 | 11 | 27 | 2 | 2 | 1 | 0.125 | 0.25 | ||||||
| Delamanid | 45 | >16 | >16 | |||||||||||
| Pretomanid | 45 | >16 | >16 | |||||||||||
| M. massiliense (29) | ||||||||||||||
| Bedaquiline | 1 | 3 | 9 | 14 | 2 | 0.125 | 0.125 | |||||||
| Delamanid | 29 | >16 | >16 | |||||||||||
| Pretomanid | 29 | >16 | >16 | |||||||||||
For DLM, M. kansasii and M. avium had the lowest MIC50 (0.03125 μg/mL and 0.125 μg/mL, respectively) values, while M. intracellulare, M. abscessus, and M. massiliense had very high MIC50 (>16 μg/mL) values. Except for M. kansasii, with lower MIC90 (0.125 μg/mL) values, all other NTM had very high MIC90 (>16 μg/mL) values.
For PA-824, M. avium, M. intracellulare, M. abscessus, and M. massiliense had very high MIC50 (>16 μg/mL) and MIC90 (>16 μg/mL) values. Compared to these NTM, M. kansasii had low MIC50 (4 μg/mL) and MIC90 (8 μg/mL) values.
Consistent with previous studies (7, 8), our results showed that all five pathogenic NTM had low MIC50 and MIC90 values against BDQ, suggesting that bedaquiline may be effective for NTM treatment. In contrast, the DLM and PA-824 MICs were high for most NTM except for M. kansasii, suggesting that these two drugs have the potential to be potent agents for the treatment of M. kansasii infection, and further studies to identify the contribution to DLM and PA-824 resistance in NTM are needed.
ACKNOWLEDGMENTS
The authors have no conflicts of interest to declare.
The project was approved by the Ethics Committee of the Chinese Center for Disease Control and Prevention.
This study was supported by the National Science and Technology Major Project, Ministry of Science and Technology of China (2018ZX10103001), and The National Major Science and Technology Project for Control and Prevention of Major Infectious Diseases in China (2017ZX10103004).
Contributor Information
Chen Shen, Email: shenchen1110@126.com.
Yanlin Zhao, Email: zhaoyl@chinacdc.cn.
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